POS0474 ACTIVATION AND HYPERSENSITIZATION OF THE ANGIOTENSIN II TYPE 1 AND ENDOTHELIN-1 TYPE A RECEPTORS BY AGONISTIC AUTOANTIBODIES CONTRIBUTES TO VASCULAR INJURY IN SCLERODERMA RENAL CRISIS
Authors: B. Hegner, R. Schindler, G. Riemekasten, P. Scheerer, A. Philippe, R. Catar
Journal: Annals of the Rheumatic Diseases (2022)

Background Scleroderma renal crisis (SRC) is a vascular complication of systemic sclerosis (SSc) with substantial risks for end-stage renal disease and death. Activating autoantibodies (Abs) targeting the angiotensin II type 1 (AT1R) and the endothelin-1 type A receptor (ETAR) are suggested to contribute to the vasculopathy in SSc (1, 2). Objectives Here, we sought to determine their pathogenic significance for acute renal vascular injury. Methods IgG from patients with SRC was studied for AT1R and ETAR dependent biologic effects on isolated rat renal interlobar arteries and vascular cells including contraction, signaling, and mechanisms of receptor activation. A cohort of ten patients with refractory SRC received multimodal treatment including AT1R and ETAR inhibition and plasma exchange and was followed for improvement of kidney function. Results In myography experiments, patient IgG exerted vasoconstriction (mean 6.5% of KCl induced contraction [95% confidence interval (95 CI) 5.0-8.1]) whereas control IgG did not (0.6% [95 CI 0.3-1.0]). The response was sensitive to inhibition of AT1R (3.0% [95% CI 1.4-4.7]) and ETAR (1.0% [95 CI 0.6-1.3]) and relied on MEK-ERK signaling. Contraction induced by angiotensin II and endothelin-1 was amplified by anti-AT1R and anti-ETAR Abs with substantial crosstalk between both receptors implicating autoimmune receptor hypersensitization. Co-immunoprecipitation experiments indicated heterodimerization between both receptor types enabling functional interrelation by structural interactions. 30% of patients with refractory SRC had improved kidney function after multimodal therapy. Conclusion We provide experimental and clinical evidence that agonistic Abs may contribute to SRC. Novel therapies targeted at autoimmune hyperactivation of AT1R and ETAR might improve outcomes in severe cases of SRC. References [1]Riemekasten, G. et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann. Rheum. Dis. 70, 530–536 (2011). [2]Becker, M. O. et al. Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am. J. Respir. Crit. Care Med. 190, 808–817 (2014). Figure 1. Contraction of isolated rat renal interlobar arteries in response to IgG isolated from patients with scleroderma renal crisis (SRC) is dependent on angiotensin II typ 1 (AT1R) and endothelin-1 type A receptors (ETAR). Small vessel myography of artery rings exposed to (a) different concentrations of IgG isolated from healthy controls (Control IgG) or patients with SRC (SRC IgG). n = 12. *P&lt;0.001 for SRC IgG versus Control IgG, #P&lt;0.01 for 1.0 mg/mL versus 0.25 mg/mL and P&lt;0.05 for 1.0 mg/mL versus 0.5 mg/mL. (b) Myography of vessels exposed to 1.0 mg/mL Control IgG or SRC IgG after pretreatment with an AT1R blocker (AT1RB, valsartan), an ETAR blocker (ETARB, sitaxsentan) or a dual endothelin-1 type A and type B receptor blocker (ETA/BRB, bosentan). n = 12. **P&lt;0.01, ***P&lt;0.001. Contraction is expressed as % of the maximal contraction in response to 60 mM KCl of each individual vessel. Mean±SEM. Figure 2. Interdependence of the angiotensin II (AngII) type 1 receptor (AT1R) and endothelin-1 (ET-1) receptors (ETA/BR) in the contractile response of isolated rat renal interlobar arteries to AngII and ET-1 in the presence of anti- AT1R and anti-ETAR activating autoantibodies. Small vessel myography of artery rings exposed to 1.0 mg/mL IgG isolated from healthy controls (Control IgG) or patients with scleroderma renal crisis (SRC IgG) and natural ligands with and without pretreatment with receptor blockers as indicated. (a) Additional stimulation with 1000 nM AngII ± ETA/BR blocker (ETA/BRB) bosentan. n = 11-18. (b) Additional stimulation with 100 nM ET-1 ± AT1R blocker (AT1RB) valsartan. n = 6-12. Contraction is expressed as % of the maximal contraction in response to 60 mM KCl of each individual vessel. Mean±SEM. **P&lt;0.01, ***P&lt;0.001. Disclosure of Interests None declared.